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Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines

Award Number: R21AI163554
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Abstract: Major Histocompatibility Complex (MHC) molecules have been long been appreciated as the bridge between the innate and adaptive immune cell populations. Beyond the peptide-presenting classical MHC class I and II molecules, there exists a variety of other structurally related proteins in humans that have been found to present diverse antigen types to a variety of T cell sub-types. Among these is the monomorphic MHC-related protein 1 (MR1) which is historically known for the presentation of microbially-derived riboflavin metabolites to Mucosal- Associated Invariant T (MAIT) cells. Expanding on this initial observation, our group and others have shown that the ligandome of MR1 is much more diverse than previously appreciated. MR1 is capable of presenting ligands of various sizes and chemical structures beyond the originally described ribityl metabolites to a vast array of MR1-restricted T cells (MR1Ts) carrying fully rearranged aß TCRs. Recently, there have been emerging reports of MR1T clones that have shown MR1-dependent cytotoxic activity against cancerous tissues in the complete absence of any microbial infection or microbial ligands. Due to the unprecedented nature of these observations and the potential impact of an MR1-based immunotherapy, it is important that the ligands being presented by MR1 in the context of cancer-induced cellular disfunction be identified. Taking into consideration our own research and these novel reports, we propose that MR1 acts as a sensor of the cellular metabolome in both the context of microbial infection and endogenous disfunction like cancer, presenting a diverse array of metabolite antigens. Due to our established track record investigating the biochemistry of MR1 and our existing collaborative ligand discovery pipeline for MR1, The Adams Lab is uniquely poised to investigate the identity of the antigens that MR1 is presenting in the context of cancer. Our investigation will focus on the plasma cell cancer, multiple myeloma, as cell lines of this cancer have been shown to have abnormally high expression of MR1 at the cell surface, indicating a higher possible antigenic load. We propose that our established microbial-ligand discovery pipeline for MR1 can be adapted to investigate the tumor associated antigens (TAAs) being presented on the surface of myeloma cells by either expressing our MR1 construct directly in these cell lines or by adding their lysate into the media of transfected producing cells; both techniques that we have used before. Identification of the ligands loaded into MR1 from these experiments will be determined by LC-MS/MS through our collaboration with the Hildebrand Lab at the Oklahoma University Health Sciences Center. Following this determination, we will capitalize on our structural biology expertise to determine how potential ligands bind the MR1 pocket. Finally, we will use MR1/TAA tetramers to stain MR1T clones from donor blood samples and investigate their transcriptional phenotype to shed light on the cognate T cell population that is reactive to these antigens.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $197,576 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	1/13/2023	NON-COMPETING CONTINUATION	$197,576
														Subtotal = $197,576

Issue Date FY: 2022 ( Subtotal = $238,576 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	1/28/2022	NEW	$238,576
														Subtotal = $238,576

Grand Total All Awards = $436,152

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Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines

Award Number: R21AI163554

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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